Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 63, Issue 2, Pages 539-550Publisher
IOS PRESS
DOI: 10.3233/JAD-171120
Keywords
Alzheimer's disease; amyloid-beta peptide; aggregation; zinc; heparin
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Funding
- Russian Science Foundation [14-24-00100]
- Russian Science Foundation [14-24-00100] Funding Source: Russian Science Foundation
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Zinc-induced aggregation of amyloid-beta peptides (A beta) is considered to contribute to the pathogenesis of Alzheimer's disease. While glycosaminoglycans (GAGs) that are commonly present in interneuronal space are known to enhance A beta self-aggregation in vitro, the impact of GAGs on the formation of zinc-induced amorphous A beta aggregates has not yet been thoroughly studied. Here, employing dynamic light scattering, bis-ANS fluorimetry, and sedimentation assays, we demonstrate that heparin serving as a representative GAG modulates the kinetics of zinc-induced A beta 42 aggregation in vitro by slowing the rate of aggregate formation and aggregate size growth. By using synthetic A beta 16 peptides to model the A beta metal-binding domain (MBD), heparin was found to effectively interact with MBDs in complex with zinc ions. We suggest that heparin adsorbs to the surface of growing zinc-induced A beta 42 aggregates via electrostatic interactions, thus creating a steric hindrance that inhibits further inclusion of monomeric and/or oligomeric zinc-A beta 42 complexes. Furthermore, the adsorbed heparin can interfere with the zinc-bridging mechanism of A beta 42 aggregation, requiring the formation of two zinc-mediated interaction interfaces in the MBD. As revealed by computer simulations of the zinc-A beta 16 homodimer complexed with a heparin chain, heparin can interact with the MBD via polar contacts with residues Arg-5 and Tyr-10, resulting in a conformational rearrangement that hampers the formation of the second zinc-mediated interaction in the MBD interface. The findings of this study suggest that GAGs, which are common in the in vivo macromolecular environment, may have a substantial impact on the time course of zinc-induced A beta aggregation.
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